JPH06239827A - 5-oxo-dibenzo(a,d)cyclohepta-1,4-diene compound - Google Patents

Abstract

The invention relates to substituted 5-oxodibenzo[a,d]cyclohepta-1,4-dienes of the general formula (I) <IMAGE> having the meaning of the substituents indicated in the description, processes for their preparation and their use as retroviral agents.

Description

Detailed Description of the Invention

The present invention relates to 5-oxo-dibenzo [a, d]
Cyclohepta-1,4-dienes, a process for their production and their use as retroviral agents.

Cis / trans-10,11-dihydroxy-5-dibenzo [a, d] cyclohepta-1,4-diene and the corresponding diacetates have already been described in Bull. Soc.
Chim. Fr. (1960), published in 400.

The present invention is based on the general formula (I)

[0004]

[Chemical 8]

[Wherein R ¹ and R ³ are the same or different and each represents an amino-protecting group, or a group of the formula R ⁷ —CO—, wherein R ⁷ is hydrogen, trifluoromethyl, or By a straight-chain or branched alkoxy having up to 8 carbon atoms or a straight-chain having up to 18 carbon atoms, which may be substituted the same or different by aryl or pyridyl having 6-10 carbon atoms at most twice. In a straight-chain or branched-chain alkyl, optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or by straight-chain or branched-chain alkyl with up to 8 carbon atoms Represents 6-10 aryl, represents a cycloalkyl having 3 to 7 carbon atoms, or is quinolyl, quinolyl N-oxide, indolyl, pyridyl or morpholino. Or it represents a piperazinyl, or formula

[0006]

[Chemical 9]

Wherein R ⁸ represents phenyl or naphthyl, R ⁹ , R ¹⁰ and R ¹¹ independently of one another have up to 14 carbon atoms which may optionally be substituted by phenyl or naphthyl. A straight or branched chain alkyl of 6 to 10 carbon atoms, or an aryl having 6 to 10 carbon atoms substituted by alkyl having up to 4 carbon atoms, R ¹⁰ is

[0008]

[Chemical 10]

## STR1 ## where m is a number 0, 1 or 2, T is morpholino or cyclohexyl, p is a number 1, 2 or 3, Y and Y'are independent of each other. CO- or SO ₂ - indicates a, t represents the number 0 or 1,
R ¹² and R ¹³ independently of each other represent hydroxyl or alkoxy having a maximum number of 8 carbons, s represents a number of 1 or 2, and R ² and R ⁴ are the same or different and each have hydrogen or a maximum number of 8 carbons. R represents a straight chain or branched chain alkyl, R
⁵ and R ⁶ are the same or different and each represent hydrogen, or each represents a linear or branched acyl or alkoxycarbonyl having up to 8 carbon atoms, or represents a hydroxyl-protecting group] Oxo-dibenzo [a, d] cyclohepta-1,4-diene, and when either R ⁵ or R ⁶ represents hydrogen, it relates to its hemiacetal form and salts thereof.

Physiologically acceptable salts of the substituted 5-oxo-dibenzo [a, d] cyclohepta-1,4-dienes are salts of the compounds according to the invention with inorganic acids, carboxylic acids or sulphonic acids. You can Particularly preferred salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, It is a salt with fumaric acid, maleic acid or benzoic acid.

Alkali metal salts (eg sodium or potassium salts), alkaline earth metal salts (eg calcium or magnesium salts), or ammonia or organic amines such as diethylamine, triethylamine,
Salts with common bases such as the ammonium salts derived from ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine can be mentioned as salts.

The compounds of the present invention may exist as stereoisomers that are image and mirror image relationships (enantiomers) or unrelated (diastereomers) to each other. The present invention relates to both antipodes and racemates, as well as diastereomeric mixtures. Racemates and diastereomers can be separated into stereoisomerically uniform components by known methods [E. L. Eliel, Stereochemis
try of Carbon Compounds, M
See cGraw Hill, 1962].

Within the scope of the present invention, amino-protecting groups are the customary amino-protecting groups used in peptide chemistry.

Preferably these are: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t
ert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1,1-
Dimethylethoxycarbonyl, adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxy. Carbonyl, formyl, acetyl,
Propionyl, pivaloyl, 2-chloroacetyl, 2-
Bromoacetyl, 2,2,2-trifluoroacetyl,
2,2,2-Trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimino, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl including.

Formula (II)

[0016]

[Chemical 11]

In the residue of the groups --OR ⁵ and --OR ⁶ can be located in the cis- or trans-position relative to each other or can be present as a mixture of cis / trans isomers.

The definition of the hemiacetal type is, for example, the formula (I
Ia):

[0019]

[Chemical 12]

Indicated by the residue

Hydroxyl-protecting groups are generally trimethylsilyl, triethylsilyl, triisopropylsilyl,
tert-butyldimethylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl,
Benzyloxycarbonyl, 2-nitrobenzyl, 4-
Nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-
Butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxycarbonyl, 2,
4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl,
[2- (trimethylsilyl) ethoxy] methyl, 2-
(Methylthiomethoxy) ethoxycarbonyl, tetrahydropyranyl or benzoyl is shown. Preferred are trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl. , Formyl, acetyl and trichloroacetyl.

In the general formula (I), R ¹ and R ³ are the same or different and are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitro. Benzyloxycarbonyl, fluorenyl-9-methoxycarbonyl or 2,
Represents 2,2-trifluoroacetyl or has the formula R ^7-
Represents a group of CO-, R ⁷ is hydrogen, trifluoromethyl,
Or a straight-chain or branched-chain alkoxy having up to 4 carbon atoms, which may be optionally substituted with phenyl, naphthyl or pyridyl up to two times in the same or differently, or a straight chain having up to 16 carbon atoms Or phenyl, which may be branched alkyl, or which may optionally be substituted by fluorine, chlorine, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl having up to 6 carbon atoms or Naphthyl, or cyclopropyl, cyclopentyl, cyclohexyl, quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or a formula

[0023]

[Chemical 13]

## STR4 ## wherein Y is CO or SO ₂
Group, R ⁸ represents phenyl or naphthyl, R ⁹ , R
¹⁰ and R ¹¹ independently of each other represent linear or branched alkyl, tolyl, phenyl or naphthyl having up to 8 carbon atoms, R ¹⁰ is of the formula

[0025]

[Chemical 14]

And m is a number of 1 or 2,
R ² and R ⁴ are the same or different and represent hydrogen, or a linear or branched alkyl having up to 6 carbon atoms, and R ⁵
And R ⁶ are the same or different and represent hydrogen, or in each case an acyl or alkoxycarbonyl having up to 6 carbon atoms, or trimethylsilyl,
Triethylsilyl, triisopropylsilyl, tert
-Butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
Preferred are formyl, acetyl or trichloroacetyl, and hemiacetal type compounds and salts thereof when either R ⁵ or R ⁶ is hydrogen.

In the formula (I), R ¹ and R ³ are the same or different and are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitrobenzyl. Oxycarbonyl, fluorenyl-9-methoxycarbonyl or 2,
Represents 2,2-trifluoroacetyl or has the formula R ^7-
Represents a group of CO--, wherein R ⁷ is hydrogen, trifluoromethyl, or a linear or branched chain having up to 4 carbon atoms which may optionally be substituted up to twice with phenyl, naphthyl or pyridyl. Alkoxy and linear or branched alkyl with up to 14 carbons, or optionally fluorine, chlorine, trifluoromethyl, trifluoromethoxy or linear or branched with up to 4 carbons Represents phenyl or naphthyl, which may be substituted by alkyl, or cyclopropyl, cyclopentyl, cyclohexyl, quinolyl, quinolyl N-
Represents an oxide, indolyl, pyridyl, morpholino or piperazinyl, or has the formula

[0028]

[Chemical 15]

## STR4 ## where Y is CO or SO ₂
A group, R ⁸ represents phenyl or naphthyl, R ⁹ and R ¹⁰ independently of each other represent linear or branched alkyl, tolyl, phenyl or naphthyl having up to 4 carbon atoms, and R ¹⁰ represents formula

[0030]

[Chemical 16]

R ² and R ⁴ are the same or different and represent hydrogen or linear or branched alkyl having up to 4 carbon atoms, and R ⁵ and R ⁶ are the same or different. Hydrogen, or in each case an acyl or alkoxycarbonyl having up to 4 carbon atoms, or trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyl Oxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, a compound showing acetyl or trichloroacetyl, and a compound of the hemiacetal type when either R ⁵ or R ⁶ represents hydrogen, and Especially those salts .

Further, the general formula (III)

[0033]

[Chemical 17]

A compound of the formula wherein R ¹⁴ and R ¹⁵ are the same or different and each represents an amino-protecting group, preferably phenylmethoxycarbonyl, is first prepared by the general formula (IV)

[0035]

Embedded image corresponding to a carboxylic acid of R ¹⁶ —CO ₂ H (IV), wherein R ¹⁶ includes respective range meanings other than hydrogen mentioned above for the substituents R ⁵ and R ^6. By reacting in the presence of a salt, general formulas (Ia) and (Ib)

[0036]

[Chemical 19]

## STR4 ## where R ¹⁴ and R ¹⁵ have the meanings given above and R ¹⁶ has the same meanings given above, but acetyl is preferred, followed by the hydroxyl function (R ⁵ / R ⁶ = H) is released by hydrolysis, and R ¹ and R ³
In the case of the remaining substituents mentioned above as radicals R ¹⁴ and R
¹⁵ is first eliminated according to the usual methods, preferably by hydrogenation, to release the amino function and, in the final step, the general formula (V)

[0038]

Embedded image A compound of R ¹⁷ —CO ₂ H (V) [wherein R ¹⁷ includes the range of the meanings of the substituents R ¹ and R ³ mentioned above] in an inert solvent and a base and / or Alternatively, in the presence of an auxiliary compound, the carboxylic acid functional group is optionally activated in advance and reacted.
A process for the preparation of compounds of general formula (I) according to the invention has been found.

For example, the method of the present invention can be illustrated by the following reaction scheme:

[0040]

[Chemical 21]

The reaction with carboxylic acids of the general formula (IV) is generally from -20 ° C to 80 ° C, preferably from 0 ° C to + 40 ° C.
Within the temperature range and at atmospheric pressure.

Acetic acid / silver acetate, propionic acid / silver propionate, or butyric acid / silver butyrate are generally suitable as carboxylic acid / salt systems. Acetic acid / silver acetate is preferred.

Customary inorganic bases are suitable bases for the hydrolysis. Preferably these include alkali metal hydroxides, alkaline earth metal hydroxides such as sodium hydride, potassium hydroxide or barium hydroxide, or alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. . The use of sodium hydroxide or potassium hydroxide is particularly preferred.

Water or an organic solvent usually used for hydrolysis is a suitable solvent for hydrolysis. Preferably these include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Particular preference is given to using alcohols such as methanol, ethanol, propanol or isopropanol. The use of mixtures of the solvents is likewise possible.

The hydrolysis is generally carried out in the temperature range of 0 ° C to + 100 ° C, preferably + 20 ° C to + 80 ° C.

Hydrolysis is generally carried out at atmospheric pressure. However, it is also possible to use reduced pressure or elevated pressure (for example 0.5-5 bar).

When carrying out the hydrolysis, generally the base is 1-3 mol, preferably 1-1.
Used in an amount of 5 mol. The use of equimolar amounts of reactants is particularly preferred.

The elimination of the amino-protecting group (R ¹⁴ / R ¹⁵ ) can be carried out in a manner known per se under acidic or basic conditions, or by ethers such as tetrahydrofuran or dioxane or methanols, alcohols such as ethanol or isopropanol. In an organic solvent such as Pd /
It is carried out reductively by catalytic hydrogenation using C.

The hydrogenation is generally carried out in the temperature range 0 ° C to 80 ° C, preferably 0 ° C to 40 ° C.

The hydrogenation is generally carried out under elevated pressure of 2 to 8 bar, preferably 3 to 5 bar.

The usual inert solvents which do not change under the reaction conditions are suitable solvents for the reaction with the compounds of the general formula (V). Preferably these include ethers such as diethyl ether, glycol mono- or dimethyl ether,
Dioxane or tetrahydrofuran, or hydrocarbons,
For example, benzene, toluene, xylene, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or Organic solvents such as picoline are included. The use of mixtures of the solvents is likewise possible. Dichloromethane, chloroform, dimethylformamide or tetrahydrofuran are particularly preferred.

Preference is given to using condensing agents as auxiliary compounds, which can also be bases, especially if the carboxylate groups are present in the activated form as the anhydride. In this case, customary condensing agents such as N, N′-diethyl-, N,
N'-diisopropyl- or N, N'-dichlorohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride or N-cyclohexyl-N '-(2-morpholinoethyl) -carbodiimide Carbodiimides such as met-p-toluenesulfonate, or carbonyl compounds such as carbonyldiimidazole, or 2-ethyl-5-
1,2-Oxazolium compounds such as phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or 2-ethoxy-1-ethoxycarbonyl-1,2- An acylamino compound such as dihydroquinoline, propanephosphonic acid anhydride, isobutyl chloroformate, benzotriazolyloxytris (dimethylamino) phosphonium hexafluorophosphate, or 1-hydroxybenzotriazole is preferable.

Further, alkali metal carbonates such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate, or organic bases such as triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine. Alkyl amines can be used. N-methylmorpholine is preferred.

The auxiliary compound and the base are respectively 1.0 mol to 3.0 mol based on 1 mol of the compound of the general formula (V).
It is used in a molar amount, preferably 1.0 to 1.2 mol.

The reaction is carried out in the temperature range of -30 ° C to 100 ° C, preferably 0 ° C to 30 ° C and under atmospheric pressure.

The reaction can be carried out both under atmospheric pressure and under elevated or reduced pressure (for example 0.5 to 5 bar), atmospheric pressure being preferred.

The compounds of the general formulas (IV) and (V) are known or can be prepared according to the usual methods.

The compounds of the general formulas (Ia) and (Ib) are new compounds and can be prepared as described above.

The compounds of the general formula (III) are likewise new compounds, firstly of the formula (VI)

[0060]

[Chemical formula 22]

2,8-Bis-azidomethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene was taken up in an ether, preferably THF, and then reacted with triphenylphosphine / water. To form a diamine, and then the general formula (VIIa) or (VIIb)

[0062]

Embedded image a compound of R ¹⁸ —CO ₂ H (VIIa) R ¹⁹ —CO—Cl (VIIb), wherein R ¹⁸ and R ¹⁹ have the above meanings for the group R ¹⁴ / R ^15. In the case of carboxylic acid (VIIa), in the case of carboxylic acid (VIIa), the carboxylic acid functional group is pre-activated and reacted in the presence of a base and an auxiliary compound, and in the final step, bromination is performed with elemental bromine in an inert solvent. It can be manufactured.

The reaction with triphenylphosphine / H ₂ O is carried out in the temperature range from 0 ° C. to + 50 ° C., preferably at room temperature,
And at atmospheric pressure.

The reaction with the compound of the general formula (VII) is carried out as described above for the reaction with the compound of the general formula (IV).

The bromination is carried out in a halogenated hydrocarbon / glacial acetic acid mixture, preferably dichloromethane / glacial acetic acid, at room temperature.

The compounds of formula (VI) are likewise new compounds, for example firstly of formula (VIII)

[0067]

[Chemical formula 24]

2,8-Dimethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene as described above in one of the solvents mentioned above, preferably in carbon tetrachloride. By the reaction with N-bromosuccinimide while irradiating with light of formula (IX)

[0069]

[Chemical 25]

It can be produced by converting to the compound of the formula (1) and reacting with lithium azide in dimethyl sulfoxide in the next step.

The bromination is carried out in the temperature range of + 50 ° C to + 120 ° C, preferably + 70 ° C to + 100 ° C.

The reaction with lithium azide is generally carried out in the temperature range 0 ° C. to + 70 ° C., preferably at room temperature.

The compounds of formula (IX) are new compounds,
Manufactured as described above.

The compound of formula (VIII) is a new compound, for example first of all formula (X)

[0075]

[Chemical formula 26]

4-methyl-2- [2- (3-methylphenyl) ethyl] benzoic acid of formula (XI) was prepared by reaction with polyphosphoric acid in sulfolane.

[0077]

[Chemical 27]

Was converted to a compound of the following and brominated with N-bromosuccinimide under irradiation with light in carbon tetrachloride as described several times in the next step, followed by hydrogen bromide under the influence of a base. Can be produced by desorption.

The reaction to give the compound of formula (X) is carried out within the temperature range of + 20 ° C to + 120 ° C, preferably 60 ° C to + 100 ° C for bromination and + 20 ° C to + 60 ° C for elimination.

The elimination is carried out in an inert solvent, preferably dimethylformamide. Preferred bases are DBN, DBU
And DABCO.

The compounds of formula (XI) are new compounds,
It can be manufactured as described above.

The compound of formula (X) is likewise a new compound, which is obtained by converting 2,4-dimethylbenzoic acid into LDA / THF / n-.
It is prepared by reacting with 3-methylbenzyl bromide in a hexane solution.

The reaction is carried out in the temperature range of -40 ° C to + 40 ° C, preferably -30 ° C to + 20 ° C.

The inhibitors described in the present text are inhibitors of HIV protease and can be used as such for all purposes for which enzyme inhibitors are suitable. This is for example used in diagnostics to improve the accuracy and selectivity of enzyme activity measurements. These can act as affinity labels in affinity chromatography and can be used in studies to elucidate the reaction mechanism and specificity of enzymatic reactions.

In addition to this, the compounds of the general formula (I) were surprisingly found to have unexpectedly strong effects against retroviruses. This is demonstrated using the HIV-specific protease enzyme test.

The results of the following examples were determined according to the HIV test system described in the following references [Hansen,
J. Billich, S .; Schulze, T .; ，
Sukrow, S .; and Moelling, K (1
988), EMBO Journal, Vol. 7, N
o. 6, pp. 1785-1791]: purified HI
V Protease was incubated with a synthetic peptide that mimics the cleavage site in the Gag precursor protein and provides an in vivo cleavage site for HIV protease. The resulting cleavage product of the synthetic peptide was analyzed using reverse phase high performance liquid chromatography (RP-HPLC). The IC ₅₀ values indicated refer to the concentration of substance which gives a 50% inhibition of the protease activity under the above-mentioned test conditions.

[0087]

[Table 1] Furthermore, the compounds of the invention showed an effect on lentivirus-infected cultured cells. This can be demonstrated using the HIV virus as an example.

HIV infection in cultured cells Pauwels et al. The HIV test was carried out according to the method of [Journal of
Virological Methods 20 , (1
988), 309-321].

Fibrinating normal human blood lymphocytes (PBL)
concentrated through coll-Hypaque, RPMI
20% containing 1640, phytohemagglutinin (90 μg / ml) and interleukin-2 (40 U / ml)
It was activated in fetal bovine serum. For infection with infectious HIV, PBLs were pelleted, after which the cell pellet was suspended in 1 ml of HIV virus adsorption solution and incubated at 37 ° C.
And incubated for 1 hour.

The virus adsorption solution was centrifuged, and the suspension was 1 ×.
The infected cell pellet was picked up in growth medium in such a way that it was adjusted to 10 ⁵ cells / ml. Cells infected in this way were pipetted into 96-well microtiter plates at 1 × 10 ⁴ cells / well.

The first vertical column of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as above (cell standard). The second vertical column of the microtiter plate shows HIV- in growth medium.
Only infected cells (virus standard) were included. The remaining wells contained compounds of the invention at different concentrations, starting with the third vertical column of the microtiter plate, from which the substance under test was diluted 2 ¹⁰ -fold in a two-fold manner.

The test mixture was treated until the appearance of syncytia formation typical of HIV in the untreated virus standard (3 after infection).
-6 days) incubated at 37 ° C. and then evaluated microscopically. Approximately 20 syncytia were produced in the untreated virus standard under these test conditions, but the untreated cell standard contained no syncytium.

The IC ₅₀ value was determined as the concentration of the compound of the invention at which 50% of the virus-induced syncytia (about 10 syncytia) were suppressed by treatment with this compound.

It has now been found that the compounds of the invention protect HIV-infected cells from virus-induced cell destruction.

[0095]

[Table 2] The compounds of the present invention provide useful active compounds for the treatment and prevention of diseases caused by retroviruses in human and veterinary medicine.

The range of instructions in human medicine that may be mentioned by way of example is: ) Treatment and prevention of human retroviral infections 1. ) HIV I (human immunodeficiency virus; formerly HT
LV III / LAV) and diseases caused by HIV II (AIDS), and the associated steps such as ARC (AIDS-related complex) and LAS (lymph node syndrome) and immunodeficiency and brain disease caused by this virus (AIDS). encephalop
athy) treatment and prevention 3. ) Treatment and prevention of HTLV-I or HTLV-II infections 4. ) AIDS-Carrier stage treatment and prophylaxis.

The animal medicine instructions that may be mentioned by way of example are: a) maezi-visna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) c) goat arthritis-encephalitis virus ( D) Zweegerz virus (in sheep and goats)
iekte virus) (in sheep) e) equine infectious anemia virus f) infection caused by simian leukemia virus g) infection caused by simian immunodeficiency virus (FIV) h) infection by simian immunodeficiency virus (SIV) is there.

Within the range of indications in human medicine, paragraphs 2, 3 and 4 above are preferred.

In addition to non-toxic and inert pharmaceutically suitable excipients, one or more of the formula (I) / (Ia) / (I
Also included in the invention are pharmaceutical compositions containing compounds of b) or containing one or more active compounds of formula (I) / (Ia) / (Ib), as well as methods of making these compositions. Be done.

Preferably the formula (I) / (Ia) / (Ib)
From about 0.1 to 99.5, preferably from about 0.5 to 95, of the total mixture in the above pharmaceutical composition.
It must be present in a concentration of% by weight.

The above pharmaceutical composition has the formula (I) / (I
As well as the compounds a) / (Ib), further pharmaceutically active compounds can be included.

The abovementioned pharmaceutical compositions are prepared in a customary manner according to known methods, for example by mixing the active compounds with excipients.

To obtain the desired results, the active compound of the invention is administered in a total amount of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight every 24 hours, optionally in several divided doses. It has been generally found that administration in the form is advantageous in both human and veterinary medicine. Each dose is about 1 to about 80, especially 1 to 3
It is preferred to include the compound in an amount of 0 mg / kg body weight. However, variations from the dosage may be necessary depending on, among other things, the nature and weight of the patient to be treated, the nature and severity of the disease, the type of composition of the drug and the type of administration, and the time period or interval between administrations. .

[0104]

Examples Starting compounds Example I 4-Methyl-2- [2- (3-methylphenyl) ethyl] benzoic acid

[0105]

[Chemical 28]

2,4-dissolved in THF (500 ml)
Dimethylbenzoic acid (54 g, 0.36 mol) was added to 10-2
Add dropwise to a solution of LDA (0.76 mol) in THF / n-hexane (1 l / 300 ml) at 0 ° C. The mixture is then stirred at room temperature for 30 minutes and cooled to -20 ° C. T
3-Methylbenzyl bromide (80 g, 0.43 mol) in HF (300 ml) is added dropwise at this temperature. The mixture is then stirred at the same temperature for 15 minutes to finish. The mixture for finishing was partitioned between hydrochloric acid and EtOAc and 2N, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with saturated NaCl, dried (MgSO _4), and concentrated in vacuo. The residue is purified on silica gel using toluene / EtOAc 10: 1 as eluent and the product obtained is crystallized from ether / petroleum ether.

Yield: 45.3 g (42% of theory) ¹ H-NMR (CDCl ₃ ): δ = 2.32 (s, 3)
H); 2.38 (s, 3H); 2.90 (m, 2H);
3.30 (m, 2H); 7.00-7.25 (m, 6
H); 8.00 (d, J = 9 Hz, 1H).

Example II 2,8-Dimethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4-diene

[0109]

[Chemical 29]

22.65 g (89 mmol) of Example I
Is heated in sulfolane (110 g) and polyphosphoric acid (460 g) at 110 ° C. for 4 hours. After cooling, the solution is poured into water (21), extracted 3 times with EtOAc, the combined organic phases are washed with water and dried (MgSO4).
₄ ). After evaporation in vacuo, chromatography on silica gel with pure toluene as eluent and the product obtained is crystallized from ether / petroleum ether.

Yield: 21.05 g (100% of theory) ¹ H-NMR (CDCl ₃ ): δ = 2.35 (s, 6)
H), 3.12 (s, 4H); 7.00 (s, 2H);
7.12 (d, J = 8Hz, 2H); 7.98 (d, J
= 8 Hz, 2H).

Example III 2,8-Dimethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene

[0113]

[Chemical 30]

21 g (88.9 mmol) of Example II
Is dissolved in tetrachloromethane (450 ml) and is illuminated with N-bromosuccinimide (19 g, 107 mmol) at 55 ° C. using a 250 W photographic lamp. After 7 hours, cool the solution and filter,
The filtrate is concentrated in vacuo and the residue is dissolved in DMF (70 ml). The solution was heated to 80 ° C. and the DBN (13.25
g, 107 mmol) are added at this temperature. 15 minutes later,
The mixture is cooled, partitioned between water and ether, the aqueous phase is extracted once with ether and the combined organic phases are 1N hydrochloric acid (3 times).
And washed with water (2 times), dried (MgSO _4), and concentrated in vacuo. The residue is crystallized from ether / petroleum ether. 11.4 g of product are obtained. An additional 2.2 g of product can be obtained from the mother liquor by chromatography on silica gel with pure toluene as eluent.

Yield: 13.6 g (65% of theory) ¹ H-NMR (CDCL ₃ ) δ = 2.46 (s, 6H);
6.95 (s, 2H); 7.32 (s, 2H); 7.4
6 (d, J = 8 Hz, 2H); 8.19 (d, J = 8H
z, 2H) Example IV 2,8-Bis-bromomethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene

[0116]

[Chemical 31]

39.8 g (170 mmol) of Example I
The compound from II and N-bromosuccinimide are heated to reflux in tetrachloromethane (1.5 l) for about 4 hours while being illuminated with a 250 W photographic lamp. The reaction is stopped when it can be observed by TLC that the desired dibromide is the main component in the mixture of starting compound, monobromide, dibromide and by-products. The insoluble material is filtered off with suction while hot and washed with tetrachloromethane. The residue is crystallized from dichloromethane, whereby 20 g
Was obtained, which is contaminated with succinimide. The first filtrate and the mother liquor from crystallization are combined, concentrated in vacuo and the residue is chromatographed on silica gel with pure toluene as eluent. 12 g
And 17 g of monobromo compound are obtained. This monobromo compound is reacted exactly with the above instructions with N-bromosuccinimide (11.6 g, 65 mmol) to give an additional 8.6 g of the desired dibromide.

Yield: 40.6 g (65.5%) ¹ H-NMR (CDCl ₃ ): δ = 4.56 (s, 4
H); 7.03 (s, 2H); 7.53 (s, 2H);
7.57 (d, J = 8 Hz, 2H); 8.20 (d, J
= 8 Hz, 2H) Example V 2,8-Bis-azidomethyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene

[0119]

[Chemical 32]

36.5 g (93 mmol) of Example IV
The compound from Example 1 is suspended in DMSO (250 ml) and then mixed with lithium azide (13.7 g, 280 mmol) at room temperature. After about 10 minutes, the solid has completely dissolved.
Finish 30 minutes later. This is EtOAc and saturated N
Worked up by partitioning between aCl, extraction of the aqueous phase with EtOAc. The organic phases are combined and washed 3 times with saturated NaCl,
Dry (MgSO ₄ ) and concentrate in vacuo at room temperature but do not dry to dryness. Mix the remaining concentrated solution with petroleum ether,
The solid obtained (15.15 g) is suction filtered. The mother liquor was concentrated and the residue was eluted with toluene / EtOAc
Chromatography on silica gel with 10: 1. This gives an additional 3.6 g of the title compound.

Yield: 18.75 g (63.5%) ¹ H-NMR (CDCl ₃ ): δ = 4.50 (s, 6)
H); 7.08 (s, 2H); 7.48 (m, 4H);
8.24 (d, J = 8 Hz, 2H) Example VI 2,8-Bis-phenylmethoxycarbonylaminomethyl-5-oxo-dibenzo [a, d] cyclohepta-
1,4,6-triene

[0122]

[Chemical 33]

Water (45 ml) and triphenylphosphine (29.5 g, 112.3 mmol) were added to THF (7
18.75 g (51.1 mmol) of the compound from Example V in (00 ml) are added and the mixture is stirred at room temperature overnight. For workup, the mixture is concentrated in vacuo, taken up in dichloromethane, the aqueous phase is separated off, the organic phase is dried (MgSO ₄ ), concentrated in vacuo and dried completely in a high vacuum. The crude diamine thus obtained was dissolved in dichloromethane (1 l) and triethylamine (3
3.3 g, 330 mmol) and benzyloxycarbonyl chloride (37.5 g, 220 mmol) are added successively. The mixture is subsequently reacted at room temperature and then 3.5
Stir for hours. For work-up, the mixture is diluted with dichloromethane (1 l), extracted once with water and suction filtered to remove solids present, after which the residue is discarded. The aqueous phase is extracted with dichloromethane and the combined organic phases are saturated with NaHC
Wash with O ₃ , dry (MgSO ₄ ) and vacuum to about 300
Concentrate to ml. The resulting jelly-like solid is suction filtered,
The mother liquor was completely concentrated, followed by toluene / E as eluent
Chromatography on silica gel with tOAc 2: 1. The fractions containing the product are concentrated and combined with the jelly obtained above. This residue is converted to hot dichloromethane /
Dissolve in 1: 1 methanol, EtOAc (200 m
1) and toluene (200 ml) are added and the mixture is concentrated in vacuo to about 100 ml. During this time an easily filterable solid precipitates, which is isolated by filtration.

Yield: 11.5 g (42% of theory) ¹ H-NMR (DMSO-d ₆ ): δ = 4.39 (d, J
= 7 Hz, 4H); 5.00 (s, 4H); 7.10
(S, 2H); 7.30 (m, 10H); 7.45
(D, J = 8 Hz, 2H); 7.51 (s, 2H);
7.91 (t, J = 7 Hz, 2H); 8.03 (d, J
= 8 Hz, 2H) Example VII 2,8-Bis-phenylmethoxycarbonylaminomethyl-10,11-dibromo-5-oxo-dibenzo [a, d] cyclohepta-1,4-diene

[0125]

[Chemical 34]

10 g (18.8 mmol) of Example VI
The compound from Example 1 and bromine (6 g, 38 mmol) are stirred overnight in dichloromethane (600 ml) and glacial acetic acid (200 ml) with exclusion of light. Then the mixture is concentrated in vacuo and the residue is taken up in toluene / EtOAc / formic acid 5:
Chromatography on silica gel with 1: 0.02.

Yield: 11.0 g (84.5% of theory) ¹ H-NMR (DMSO-d ₆ ): δ = 4.30 (d, J
= 7 Hz, 4H); 5.08 (s, 4H); 6.12
(S, 2H); 7.35 (m, 12H); 7.95
(M, 4H) Preparation Examples Example 1, Example 2 and Example 3 (trans) -2,8-bis-phenylmethoxycarbonylaminomethyl-10,11-diacetoxy-5-oxo-dibenzo [a, d]. Cyclohepta-1,4-diene

[0128]

[Chemical 35]

(Cis) -10-acetoxy-2,8-bis-phenylmethoxycarbonylaminomethyl-11-
Hydroxy-5-oxo-dibenzo [a, d] cyclohepta-1,4-diene

[0130]

[Chemical 36]

(Cis) -11-acetoxy-5-hydroxy-2,8-bis-phenylmethoxycarbonylaminomethyl-dibenzo [b, e] bicyclo [2.1.3]
1-oxaoctane

[0132]

[Chemical 37]

2.44 g (3.53 mmol) of the compound of Example VII and silver acetate (1.77 g, 10.6 mmol) were heated to reflux with dry acetic acid (100 ml, 150 ml acetic acid and 10 ml acetic anhydride for 1 hour). And under reflux for 3 hours. The mixture is subsequently cooled,
Filter to remove solids and concentrate the filtrate in vacuo. The residue is chromatographed on silica gel with toluene / ethyl acetate 2: 1 as eluent. This elutes the trans compound (Example 1). The cis component (Example 2) is subsequently eluted with ethyl acetate / acetone 1: 1.

Example 1 Yield: 1.57 g (68.5% of theory) ¹ H-NMR (DMSO-d ₆ ): δ = 1.82 (s, 6)
H); 4.28 (d, J = 7 Hz, 4H); 5.05
(S, 4H); 6.21 (s, 2H); 7.35 (m,
14H); 7.82 (d, J = 8Hz, 2H); 7.9
5 (t, J = 7 Hz, 2 H) Example 2 Yield: 0.43 g (20% of theory) ¹ H-NMR (DMSO-d ₆ ): δ = 2.02 (s, 3)
H); 4.29 (d, J = 7 Hz, 4H); 5.06
(M, 5H); 6.12 (s, 1H); 6.19 (d,
J = 5 Hz, 1H); 7.31 (m, 13H); 7.5
0 (s, 1H); 7.73 (d, J = 8Hz, 1H);
7.79 (d, J = 8 Hz, 1H); 7.96 (t, J
= 7 Hz, 2H) 11% of the compound of Example 3 in equilibrium with Example 2 together with 89% of the compound from Example 2 is observed by ¹ H-NMR. Characteristic signal: ¹ H-NMR (DMSO
−d ₆ ): δ = 4.10 (d, J = 2 Hz, 2H);
4.19 (d, J = 7 Hz, 2H); 5.42 (s, 1
H); 7.00-7.25 (m, 6H) Example 4 (trans) -2,8-bis-phenylmethoxycarbonylaminomethyl-10,11-dihydroxy-5-oxo-dibenzo [a, d]. Cyclohepta-1,4-diene

[0135]

[Chemical 38]

0.1 N NaOH (126 ml) was added to 1.8 (2.76 mmol) in ethanol (180 ml).
In addition to the compound from Example 1 above, the mixture is stirred at room temperature for 1 hour. The alcohol is subsequently evaporated in vacuo and the aqueous phase is extracted 3 times with EtOAc. The combined organic phases were washed with saturated NaCl, dried (MgSO _4), and concentrated in vacuo. The residue is stirred with dichloromethane and the solid obtained (1.38 g) is suction filtered. Concentrate the mother liquor,
Chromatography on silica gel with toluene / ethyl acetate 1: 1 then 1: 2 as eluent. This gives a further 0.18 g of product.

MS (FAB): 567 (M ⁺ + H, 10
0%) ¹ H-NMR (DMSO-d ₆ ): δ = 4.26 (d, J
= 7 Hz, 4H); 4.86 (m, 2H); 5.08
(S, 4H); 5.82 (m, 2H); 7.23 (d,
J = 8 Hz, 2H); 7.25 (s, 2H); 7.32
(S, 10H); 7.65 (d, J = 8Hz, 2H);
7.93 (t, J = 7 Hz, 2H) With 94% of the compound of Example 4, 6% of the isomeric hemiacetal is also observed in ¹ H-NMR as in Example 3. Characteristic signal: ¹ H-NMR (DMS
_{O-d 6): δ =} 4.10 (d, J = 7Hz, 2H);
4.17 (dm, J = 7 Hz, 2H); 5.02 (m,
1H); 5.22 (d, J = 6 Hz, 1H); 5.76
(D, J = 5 Hz, 1H); 7.80 (s, 1H, O
H) Example 5 (cis) -2,8-bis-phenylmethoxycarbonylaminomethyl-10,11-dihydroxy-5-oxo-dibenzo [a, d] cyclohepta-1,4-diene

[0138]

[Chemical Formula 39]

This compound is prepared from the compound of Example 2 in analogy to the instructions in Example 4.

Yield: 81% ¹ H-NMR (DMSO-d ₆ ): δ = 4.28 (d, J
= 7 Hz, 4 H); 4.89 (d, J = 6 Hz, 2
H); 5.07 (s, 4H); 5.70 (d, J = 6H
z, 2H); 7.23 (d, J = 8Hz, 2H);
32 (s, 10H); 7.50 (s, 2H); 7.73
(D, J = 8 Hz, 2H); 7.94 (t, J = 7H
z, 2H) 9% of the isomeric hemiacetal is observed in ¹ H-NMR with 91% of the compound from Example 4 as in Example 3. Characteristic signal: ¹ H-NMR (DM
_{SO-d 6): δ =} 4.10 (d, J = 7Hz, 2
H); 4.17 (d, J = 7 Hz, 2H); 5.02
(M, 1H); 5.28 (s, 1H); 7.86 (s,
1H, OH) Example 6 (trans) -10,11-dihydroxy-2,8-bis- [5,5-dimethyl-4,4-dioxo-2- (1
-Naphthylmethyl) -4-thiahexanoylaminomethyl-5-oxo-dibenzo [a, d] cyclohepta-
1,4-diene

[0141]

[Chemical 40]

200 mg (0.35 mmol) of the compound from Example 4 in methanol (100 ml) and 10
2. under 1 bar in the presence of% Pd / C (40 mg).
Hydrogenate for 5 hours. The mixture is subsequently filtered to remove the catalyst and the filtrate is concentrated in vacuo. HOBT (95 mg,
0.70 mmol) and DCC (160 mg, 0.78)
Mmol) in THF (4 ml) with 5,5-dimethyl-
4,4-dioxo-2- (1-naphthylmethyl) -4-
To thiahexanoic acid (235 mg, 0.70 mmol),
Add while cooling with ice. The mixture is subsequently stirred at room temperature for 1 hour and then added to the crude diamine (obtained above by hydrogenation) in dichloromethane (2 ml). The mixture is subsequently stirred at room temperature for 5 hours, after which EtOAc (150 m
Dilute with l). The solution was added to 4% acetic acid (25 m
l), washed with saturated NaHCO ₃ and saturated NaCl, then dried (MgSO ₄ ) and concentrated in vacuo. The residue is purified on silica gel with EtOAc / acetic acid 5: 1, then 5: 2. A jelly-like product is obtained which is triturated thoroughly with dichloromethane and crystallized. Further products can be obtained by dissolving the mother liquor in acetone / methanol, adding ether and crystallizing in a refrigerator.

Yield: 46 mg (14% of theory) ¹ H-NMR (DMSO-d ₆ ): δ = 1.24 (s, 9)
H); 3.10 (dd, J = 14 Hz and 3 Hz, 2
H); 3.35 (m, 6H); 3.59 (dd, J = 1
4 Hz and 6 Hz, 2H); 4.16 (dd, J = 16)
And 5 Hz, 2H); 4.30 (dd, J = 16 Hz and 5 Hz, 2H); 4.82 (m, 2H); 5.71
(M, 2H); 6.88 (d, J = 8Hz, 2H);
7.21 (s, 2H); 7.30-7.60 (m, 10)
H), 7.83 (d, J = 8 Hz, 2H); 7.95
(D, J = 8 Hz, 2H); 8.24 (d, J = 7H
z, 2H); 8.64 (t, J = 5Hz, 2H) The compounds listed in Table 1 are prepared in analogy to the instructions of Example 6:

[0144]

[Table 3]

Example 11 (trans) -10,11-bis- (tert-butyldimethylsilyloxy) -2,8-bis-phenylmethoxycarbonylaminomethyl-5-oxo-dibenzo [a, d] cyclohepta-1 , 4-diene

[0146]

[Chemical 41]

4 g of imidazole (1.9 g, 28.4 mmol) and tert-butyldimethylsilyl chloride (2.35 g, 15.6 mmol) at room temperature.
(7.1 mmol) of the compound from Example 4 is added, after which the mixture is stirred at 50 ° C. for 2.5 hours. The mixture was diluted with EtOAc for workup, washed with water, twice with 1N hydrochloric acid and saturated NaCl, then dried (MgSO 4.
₄ ) and concentrate in vacuo. The residue is purified on silica gel with toluene / EtOAc 10: 1 as eluent.

Yield: 5.1 g (90.5% of theory) ¹ H-NMR (CDCl ₃ ): δ = 0.19 (s, 6)
H); 0.07 (s, 6H); 0.61 (s, 18
H); 4.42 (d, J = 6 Hz, 4H); 4.93
(S, 2H); 5.04 (t, br, J = 6Hz, 2
H); 5.15 (s, 4H); 7.15 (s, 2H);
7.24 (m, 2H); 7.35 (m, 10H);
89 (d, J = 8 Hz, 2H) Example 12 (trans) -10,11-dihydroxy-2,8-bis- [methyl (phenylmethoxycarbonyl) amino]
Methyl-5-oxo-dibenzo [a, d] cyclohepta-1,4,6-triene

[0149]

[Chemical 42]

35% potassium hydride suspension (11.3
mg, 0.283 mmol) and methyl iodide (48 m
g, 0.34 mmol) 90 m in DMF (9 ml)
g (0.113 mmol) to the compound of Example 11 is added with ice cooling. After 15 minutes at the same temperature, finishing is performed. The mixture was partitioned between EtOAc and 1N hydrochloric acid and the aqueous phase was Et.
Extract with OAc, wash the combined organic phases with saturated NaCl, dry (MgSO ₄ ) and concentrate in vacuo. The residue is purified on silica gel with toluene / EtOAc 10: 1 as eluent. Intermediates of 48mg is obtained, to remove the silyl protecting group according to the general methods for the removal of the silyl group _{(n-Bu 4 NF, THF} , room temperature).

Yield: 22 mg (33% of theory) ¹ H-NMR (CDCl ₃ ): δ = 3.86 and 3.92
(2s, 6H); 4.52 (s, 4H); 4.90 (b
r, 2H); 5.17 (s, 4H); 7.20-7.4.
0 (m, 14H); 7.46 and 7.58 (2br, 2
H); 7.84 (d, J = 8 Hz, 2H) The main features and aspects of the present invention are as follows.

1. General formula (I)

[0153]

[Chemical 43]

[Wherein R ¹ and R ³ are the same or different and each represents an amino-protecting group, or a group of the formula R ⁷ —CO—, wherein R ⁷ is hydrogen, trifluoromethyl, or By a straight-chain or branched alkoxy having up to 8 carbon atoms or a straight-chain having up to 18 carbon atoms, which may be substituted the same or different by aryl or pyridyl having 6-10 carbon atoms at most twice. In a straight-chain or branched-chain alkyl, optionally substituted by halogen, trifluoromethyl, trifluoromethoxy or by straight-chain or branched-chain alkyl with up to 8 carbon atoms Represents 6-10 aryl, represents a cycloalkyl having 3 to 7 carbon atoms, or is quinolyl, quinolyl N-oxide, indolyl, pyridyl or morpholino. Or it represents a piperazinyl, or formula

[0155]

[Chemical 44]

Wherein R ⁸ represents phenyl or naphthyl, R ⁹ , R ¹⁰ and R ¹¹ independently of one another have up to 14 carbon atoms which may optionally be substituted by phenyl or naphthyl. A straight or branched chain alkyl of 6 to 10 carbon atoms, or an aryl having 6 to 10 carbon atoms substituted by alkyl having up to 4 carbon atoms, R ¹⁰ is

[0157]

[Chemical formula 45]

Represents a residue of m, represents a number of 0, 1 or 2, T represents morpholino or cyclohexyl, p represents a number of 1, 2 or 3, and Y and Y'independently from each other. CO- or SO ₂ - indicates a, t represents the number 0 or 1,
R ¹² and R ¹³ independently of each other represent hydroxyl or alkoxy having a maximum number of 8 carbons, s represents a number of 1 or 2, and R ² and R ⁴ are the same or different and each have hydrogen or a maximum number of 8 carbons. R represents a straight chain or branched chain alkyl, R
⁵ and R ⁶ are the same or different and each represent hydrogen, or each represents a linear or branched acyl or alkoxycarbonyl having up to 8 carbon atoms, or a hydroxyl-protecting group] - dibenzo [a, d] cyclohepta-1,4-diene, and R ⁵ or any of the R ⁶ represents hydrogen, the hemiacetal form and salts thereof.

2. In the general formula (I), R ¹ and R ³ are the same or different and benzyloxycarbonyl, 4-
Methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl,
Represents allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, fluorenyl-9-methoxycarbonyl or 2,2,2-trifluoroacetyl, or has the formula R
Represents a ^7- CO- group, R ⁷ is hydrogen, trifluoromethyl, or a straight chain having up to 4 carbon atoms which may be optionally substituted by phenyl, naphthyl or pyridyl up to 2 times. Linear or branched alkoxy, or linear or branched alkyl having up to 16 carbon atoms, or optionally fluorine, chlorine, trifluoromethyl, trifluoromethoxy or a straight chain having up to 6 carbon atoms. Represents phenyl or naphthyl, which may be substituted by chain or branched alkyl, or represents cyclopropyl, cyclopentyl, cyclohexyl, quinolyl, quinolyl N-oxide, indolyl, pyridyl, morpholino or piperazinyl, or formula

[0160]

[Chemical formula 46]

Wherein Y is CO or SO ₂
Group, R ⁸ represents phenyl or naphthyl, R ⁹ , R
¹⁰ and R ¹¹ independently of each other represent linear or branched alkyl, tolyl, phenyl or naphthyl having up to 8 carbon atoms, R ¹⁰ is of the formula

[0162]

[Chemical 47]

And m is a number of 1 or 2,
R ² and R ⁴ are the same or different and represent hydrogen, or a linear or branched alkyl having up to 6 carbon atoms, and R ⁵
And R ⁶ are the same or different and represent hydrogen, or in each case an acyl or alkoxycarbonyl having up to 6 carbon atoms, or trimethylsilyl,
Triethylsilyl, triisopropylsilyl, tert
-Butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
The compound according to item 1 above, which represents formyl, acetyl or trichloroacetyl, and the hemiacetal type compounds and salts thereof when either R ⁵ or R ⁶ represents hydrogen.

3. In the formula (I), R ¹ and R ³ are the same or different and are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 2-nitrobenzyloxycarbonyl, Fluorenyl-9-methoxycarbonyl or 2,
Represents 2,2-trifluoroacetyl or has the formula R ^7-
Represents a group of CO--, wherein R ⁷ is hydrogen, trifluoromethyl, or a linear or branched chain having up to 4 carbon atoms which may optionally be substituted up to twice with phenyl, naphthyl or pyridyl. Alkoxy and linear or branched alkyl with up to 14 carbons, or optionally fluorine, chlorine, trifluoromethyl, trifluoromethoxy or linear or branched with up to 4 carbons Represents phenyl or naphthyl, which may be substituted by alkyl, or cyclopropyl, cyclopentyl, cyclohexyl, quinolyl, quinolyl N-
Represents an oxide, indolyl, pyridyl, morpholino or piperazinyl, or has the formula

[0165]

[Chemical 48]

Wherein Y is CO or SO ₂
A group, R ⁸ represents phenyl or naphthyl, R ⁹ and R ¹⁰ independently of each other represent linear or branched alkyl, tolyl, phenyl or naphthyl having up to 4 carbon atoms, and R ¹⁰ represents formula

[0167]

[Chemical 49]

R ² and R ⁴ are the same or different and represent hydrogen, or linear or branched alkyl having up to 4 carbon atoms, and R ⁵ and R ⁶ are the same or different. Hydrogen, or in each case an acyl or alkoxycarbonyl having up to 4 carbon atoms, or trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, triphenylsilyl, benzyloxycarbonyl, 4-nitrobenzyl Oxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl or trichloroacetyl, the compound according to the above item 1, and R ⁵ or R ⁶
When either of the above indicates hydrogen, the hemiacetal type compounds and salts thereof.

4. General formula (III)

[0170]

[Chemical 50]

A compound of the formula: wherein R ¹⁴ and R ¹⁵ are the same or different and each represents an amino-protecting group, preferably phenylmethoxycarbonyl, is firstly represented by the general formula (IV)

[0172]

Corresponding to a carboxylic acid of R ¹⁶ —CO ₂ H (IV), wherein R ¹⁶ has the meaning of the respective ranges other than hydrogen mentioned above for the substituents R ⁵ and R ^6. By reacting in the presence of a salt, general formulas (Ia) and (Ib)

[0173]

[Chemical 52]

## STR14 ## where R ¹⁴ and R ¹⁵ have the meanings given above and R ¹⁶ has the same meanings given above, but acetyl is preferred, followed by the hydroxyl function (R ⁵ / R ⁶ = H) is released by hydrolysis, and R ¹ and R ³
In the case of the remaining substituents mentioned above as radicals R ¹⁴ and R
¹⁵ is first eliminated according to the usual methods, preferably by hydrogenation, to release the amino function and, in the final step, the general formula (V)

[0175]

Embedded image A compound of R ¹⁷ —CO ₂ H (V) [in the formula, R ¹⁷ includes the scope of the meanings of the substituents R ¹ and R ³ mentioned above] in an inert solvent and a base and / or Alternatively, in the presence of the auxiliary compound, the carboxylic acid functional group is optionally activated in advance to react, and the method for producing the compound of the general formula (I) according to item 1 above.

5. A drug containing one or more of the compounds according to the above item 1.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical indication location A61K 31/535 7431-4C 31/66 8314-4C 31/675 8314-4C C07C 233/33 7106-4H 311 / 06 7419-4H 317/28 7419-4H C07D 209/18 9284-4C 215/48 295/20 Z 493/08 9165-4C B 9165-4C C07F 7/18 A 8018-4H (72) Inventor Jerck Lautz Federal Republic of Germany Day 42489 Biulfurt Frieugelskemphen 16 (72) Inventor Arnold Pesens Federal Republic of Germany Day 42781 Khan Scheu Trezemann Schyutraße 56

Claims (3)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ and R ³ are the same or different and each represents an amino-protecting group, or a group of the formula R ⁷ —CO—, wherein R ⁷ is hydrogen, trifluoromethyl, or optionally a carbon number. Is a linear or branched alkoxy having up to 8 carbon atoms, which may be substituted up to twice with the same or different aryl or pyridyl of 6-10, or a linear or branched chain having up to 18 carbon atoms. Branched alkyl, or optionally halogen, trifluoromethyl,
Trifluoromethoxy or with up to 8 carbons
Represents an aryl having 6 to 10 carbon atoms, which may be substituted by a straight chain or branched alkyl of, a cycloalkyl having 3 to 7 carbon atoms, or quinolyl, quinolyl N-oxide, Represents indolyl, pyridyl, morpholino or piperazinyl, or has the formula: Wherein R ⁸ represents phenyl or naphthyl, and R ⁹ , R ¹⁰ and R ¹¹ independently of one another are straight-chain with up to 14 carbon atoms which may optionally be substituted by phenyl or naphthyl. A branched or branched alkyl, or an aryl of 6-10 carbons substituted with an alkyl of up to 4 carbons, R ¹⁰ is of the formula: Represents a residue of, m represents a number of 0, 1 or 2, T represents a morpholino or cyclohexyl, p represents a number of 1, 2 or 3, Y and Y'independently of each other CO- or SO ₂ −, t represents a number of 0 or 1, R ¹² and R ¹³ independently of each other represent hydroxyl or alkoxy having up to 8 carbon atoms, s represents a number of 1 or 2, R ² And R ⁴ are the same or different and represent hydrogen or a linear or branched alkyl having up to 8 carbon atoms, and R ⁵ and R ⁶ are the same or different from hydrogen, or each has up to 8 carbon atoms. Represents a linear or branched acyl or alkoxycarbonyl of
Or represents a hydroxyl-protecting group]
Dibenzo [a, d] cyclohepta-1,4-diene, and when either R ⁵ or R ⁶ represents hydrogen, its hemiacetal form and salts thereof. 2. A compound represented by the general formula (III): A compound of the formula: wherein R ¹⁴ and R ¹⁵ are the same or different and each represents an amino-protecting group, preferably phenylmethoxycarbonyl, is first represented by the general formula (IV) embedded image R ¹⁶ —CO ₂ H (IV) [Wherein R ¹⁶ includes the respective meanings of ranges other than hydrogen mentioned above for the substituents R ⁵ and R ⁶ ] in the presence of a corresponding salt to give a compound of the general formula ( Ia) and (Ib) embedded image Where R ¹⁴ and R ¹⁵ have the meanings given above and R ¹⁶ has the same meanings given above, but is preferably acetyl, and is subsequently converted to the hydroxyl function (R ⁵ / R ⁶ = H)
In the case of the remaining substituents mentioned above as R ¹ and R ^{3 which} are liberated by hydrolysis, the radicals R ¹⁴ and R ¹⁵ are first removed in a conventional manner, preferably by hydrogenation, to give an amino functional group. It is liberated and, in the final step, is of the general formula (V) ## STR7 ## R ¹⁷ --CO ₂ H (V) where R ¹⁷ includes the meanings of the substituents R ¹ and R ³ mentioned above. The compound of the general formula (I) according to claim 1, wherein the compound of claim 1 is reacted in the presence of a base and / or an auxiliary compound in an inert solvent, if necessary by previously activating the carboxylic acid functional group. Manufacturing method. 3. A drug containing one or more of the compounds according to claim 1.